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1.  High-Dimensional Additive Hazards Regression for Oral Squamous Cell Carcinoma Using Microarray Data: A Comparative Study 
BioMed Research International  2014;2014:393280.
Microarray technology results in high-dimensional and low-sample size data sets. Therefore, fitting sparse models is substantial because only a small number of influential genes can reliably be identified. A number of variable selection approaches have been proposed for high-dimensional time-to-event data based on Cox proportional hazards where censoring is present. The present study applied three sparse variable selection techniques of Lasso, smoothly clipped absolute deviation and the smooth integration of counting, and absolute deviation for gene expression survival time data using the additive risk model which is adopted when the absolute effects of multiple predictors on the hazard function are of interest. The performances of used techniques were evaluated by time dependent ROC curve and bootstrap .632+ prediction error curves. The selected genes by all methods were highly significant (P < 0.001). The Lasso showed maximum median of area under ROC curve over time (0.95) and smoothly clipped absolute deviation showed the lowest prediction error (0.105). It was observed that the selected genes by all methods improved the prediction of purely clinical model indicating the valuable information containing in the microarray features. So it was concluded that used approaches can satisfactorily predict survival based on selected gene expression measurements.
PMCID: PMC4055233  PMID: 24982876
2.  Supervised group Lasso with applications to microarray data analysis 
BMC Bioinformatics  2007;8:60.
A tremendous amount of efforts have been devoted to identifying genes for diagnosis and prognosis of diseases using microarray gene expression data. It has been demonstrated that gene expression data have cluster structure, where the clusters consist of co-regulated genes which tend to have coordinated functions. However, most available statistical methods for gene selection do not take into consideration the cluster structure.
We propose a supervised group Lasso approach that takes into account the cluster structure in gene expression data for gene selection and predictive model building. For gene expression data without biological cluster information, we first divide genes into clusters using the K-means approach and determine the optimal number of clusters using the Gap method. The supervised group Lasso consists of two steps. In the first step, we identify important genes within each cluster using the Lasso method. In the second step, we select important clusters using the group Lasso. Tuning parameters are determined using V-fold cross validation at both steps to allow for further flexibility. Prediction performance is evaluated using leave-one-out cross validation. We apply the proposed method to disease classification and survival analysis with microarray data.
We analyze four microarray data sets using the proposed approach: two cancer data sets with binary cancer occurrence as outcomes and two lymphoma data sets with survival outcomes. The results show that the proposed approach is capable of identifying a small number of influential gene clusters and important genes within those clusters, and has better prediction performance than existing methods.
PMCID: PMC1821041  PMID: 17316436
3.  Variable selection in the accelerated failure time model via the bridge method 
Lifetime data analysis  2009;16(2):176-195.
In high throughput genomic studies, an important goal is to identify a small number of genomic markers that are associated with development and progression of diseases. A representative example is microarray prognostic studies, where the goal is to identify genes whose expressions are associated with disease free or overall survival. Because of the high dimensionality of gene expression data, standard survival analysis techniques cannot be directly applied. In addition, among the thousands of genes surveyed, only a subset are disease-associated. Gene selection is needed along with estimation. In this article, we model the relationship between gene expressions and survival using the accelerated failure time (AFT) models. We use the bridge penalization for regularized estimation and gene selection. An efficient iterative computational algorithm is proposed. Tuning parameters are selected using V-fold cross validation. We use a resampling method to evaluate the prediction performance of bridge estimator and the relative stability of identified genes. We show that the proposed bridge estimator is selection consistent under appropriate conditions. Analysis of two lymphoma prognostic studies suggests that the bridge estimator can identify a small number of genes and can have better prediction performance than the Lasso.
PMCID: PMC2989175  PMID: 20013308
Bridge penalization; Censored data; High dimensional data; Selection consistency; Stability; Sparse model
4.  Buckley-James Boosting for Survival Analysis with High-Dimensional Biomarker Data* 
There has been increasing interest in predicting patients’ survival after therapy by investigating gene expression microarray data. In the regression and classification models with high-dimensional genomic data, boosting has been successfully applied to build accurate predictive models and conduct variable selection simultaneously. We propose the Buckley-James boosting for the semiparametric accelerated failure time models with right censored survival data, which can be used to predict survival of future patients using the high-dimensional genomic data. In the spirit of adaptive LASSO, twin boosting is also incorporated to fit more sparse models. The proposed methods have a unified approach to fit linear models, non-linear effects models with possible interactions. The methods can perform variable selection and parameter estimation simultaneously. The proposed methods are evaluated by simulations and applied to a recent microarray gene expression data set for patients with diffuse large B-cell lymphoma under the current gold standard therapy.
PMCID: PMC2904263  PMID: 20597850
boosting; accelerated failure time model; Buckley-James estimator; censored survival data; LASSO; variable selection
5.  Gene Selection using a High-Dimensional Regression Model with Microarrays in Cancer Prognostic Studies 
Cancer Informatics  2012;11:29-39.
Mining of gene expression data to identify genes associated with patient survival is an ongoing problem in cancer prognostic studies using microarrays in order to use such genes to achieve more accurate prognoses. The least absolute shrinkage and selection operator (lasso) is often used for gene selection and parameter estimation in high-dimensional microarray data. The lasso shrinks some of the coefficients to zero, and the amount of shrinkage is determined by the tuning parameter, often determined by cross validation. The model determined by this cross validation contains many false positives whose coefficients are actually zero. We propose a method for estimating the false positive rate (FPR) for lasso estimates in a high-dimensional Cox model. We performed a simulation study to examine the precision of the FPR estimate by the proposed method. We applied the proposed method to real data and illustrated the identification of false positive genes.
PMCID: PMC3298378  PMID: 22442625
cancer prognostic; false positive rate; gene selection; high-dimensional regression; microarray data; survival analysis
6.  Genomic selection using regularized linear regression models: ridge regression, lasso, elastic net and their extensions 
BMC Proceedings  2012;6(Suppl 2):S10.
Genomic selection (GS) is emerging as an efficient and cost-effective method for estimating breeding values using molecular markers distributed over the entire genome. In essence, it involves estimating the simultaneous effects of all genes or chromosomal segments and combining the estimates to predict the total genomic breeding value (GEBV). Accurate prediction of GEBVs is a central and recurring challenge in plant and animal breeding. The existence of a bewildering array of approaches for predicting breeding values using markers underscores the importance of identifying approaches able to efficiently and accurately predict breeding values. Here, we comparatively evaluate the predictive performance of six regularized linear regression methods-- ridge regression, ridge regression BLUP, lasso, adaptive lasso, elastic net and adaptive elastic net-- for predicting GEBV using dense SNP markers.
We predicted GEBVs for a quantitative trait using a dataset on 3000 progenies of 20 sires and 200 dams and an accompanying genome consisting of five chromosomes with 9990 biallelic SNP-marker loci simulated for the QTL-MAS 2011 workshop. We applied all the six methods that use penalty-based (regularization) shrinkage to handle datasets with far more predictors than observations. The lasso, elastic net and their adaptive extensions further possess the desirable property that they simultaneously select relevant predictive markers and optimally estimate their effects. The regression models were trained with a subset of 2000 phenotyped and genotyped individuals and used to predict GEBVs for the remaining 1000 progenies without phenotypes. Predictive accuracy was assessed using the root mean squared error, the Pearson correlation between predicted GEBVs and (1) the true genomic value (TGV), (2) the true breeding value (TBV) and (3) the simulated phenotypic values based on fivefold cross-validation (CV).
The elastic net, lasso, adaptive lasso and the adaptive elastic net all had similar accuracies but outperformed ridge regression and ridge regression BLUP in terms of the Pearson correlation between predicted GEBVs and the true genomic value as well as the root mean squared error. The performance of RR-BLUP was also somewhat better than that of ridge regression. This pattern was replicated by the Pearson correlation between predicted GEBVs and the true breeding values (TBV) and the root mean squared error calculated with respect to TBV, except that accuracy was lower for all models, most especially for the adaptive elastic net. The correlation between the predicted GEBV and simulated phenotypic values based on the fivefold CV also revealed a similar pattern except that the adaptive elastic net had lower accuracy than both the ridge regression methods.
All the six models had relatively high prediction accuracies for the simulated data set. Accuracy was higher for the lasso type methods than for ridge regression and ridge regression BLUP.
PMCID: PMC3363152  PMID: 22640436
7.  New bandwidth selection criterion for Kernel PCA: Approach to dimensionality reduction and classification problems 
BMC Bioinformatics  2014;15:137.
DNA microarrays are potentially powerful technology for improving diagnostic classification, treatment selection, and prognostic assessment. The use of this technology to predict cancer outcome has a history of almost a decade. Disease class predictors can be designed for known disease cases and provide diagnostic confirmation or clarify abnormal cases. The main input to this class predictors are high dimensional data with many variables and few observations. Dimensionality reduction of these features set significantly speeds up the prediction task. Feature selection and feature transformation methods are well known preprocessing steps in the field of bioinformatics. Several prediction tools are available based on these techniques.
Studies show that a well tuned Kernel PCA (KPCA) is an efficient preprocessing step for dimensionality reduction, but the available bandwidth selection method for KPCA was computationally expensive. In this paper, we propose a new data-driven bandwidth selection criterion for KPCA, which is related to least squares cross-validation for kernel density estimation. We propose a new prediction model with a well tuned KPCA and Least Squares Support Vector Machine (LS-SVM). We estimate the accuracy of the newly proposed model based on 9 case studies. Then, we compare its performances (in terms of test set Area Under the ROC Curve (AUC) and computational time) with other well known techniques such as whole data set + LS-SVM, PCA + LS-SVM, t-test + LS-SVM, Prediction Analysis of Microarrays (PAM) and Least Absolute Shrinkage and Selection Operator (Lasso). Finally, we assess the performance of the proposed strategy with an existing KPCA parameter tuning algorithm by means of two additional case studies.
We propose, evaluate, and compare several mathematical/statistical techniques, which apply feature transformation/selection for subsequent classification, and consider its application in medical diagnostics. Both feature selection and feature transformation perform well on classification tasks. Due to the dynamic selection property of feature selection, it is hard to define significant features for the classifier, which predicts classes of future samples. Moreover, the proposed strategy enjoys a distinctive advantage with its relatively lesser time complexity.
PMCID: PMC4025604  PMID: 24886083
8.  Iterative Bayesian Model Averaging: a method for the application of survival analysis to high-dimensional microarray data 
BMC Bioinformatics  2009;10:72.
Microarray technology is increasingly used to identify potential biomarkers for cancer prognostics and diagnostics. Previously, we have developed the iterative Bayesian Model Averaging (BMA) algorithm for use in classification. Here, we extend the iterative BMA algorithm for application to survival analysis on high-dimensional microarray data. The main goal in applying survival analysis to microarray data is to determine a highly predictive model of patients' time to event (such as death, relapse, or metastasis) using a small number of selected genes. Our multivariate procedure combines the effectiveness of multiple contending models by calculating the weighted average of their posterior probability distributions. Our results demonstrate that our iterative BMA algorithm for survival analysis achieves high prediction accuracy while consistently selecting a small and cost-effective number of predictor genes.
We applied the iterative BMA algorithm to two cancer datasets: breast cancer and diffuse large B-cell lymphoma (DLBCL) data. On the breast cancer data, the algorithm selected a total of 15 predictor genes across 84 contending models from the training data. The maximum likelihood estimates of the selected genes and the posterior probabilities of the selected models from the training data were used to divide patients in the test (or validation) dataset into high- and low-risk categories. Using the genes and models determined from the training data, we assigned patients from the test data into highly distinct risk groups (as indicated by a p-value of 7.26e-05 from the log-rank test). Moreover, we achieved comparable results using only the 5 top selected genes with 100% posterior probabilities. On the DLBCL data, our iterative BMA procedure selected a total of 25 genes across 3 contending models from the training data. Once again, we assigned the patients in the validation set to significantly distinct risk groups (p-value = 0.00139).
The strength of the iterative BMA algorithm for survival analysis lies in its ability to account for model uncertainty. The results from this study demonstrate that our procedure selects a small number of genes while eclipsing other methods in predictive performance, making it a highly accurate and cost-effective prognostic tool in the clinical setting.
PMCID: PMC2657791  PMID: 19245714
9.  Unravelling the hidden heterogeneities of diffuse large B-cell lymphoma based on coupled two-way clustering 
BMC Genomics  2007;8:332.
It becomes increasingly clear that our current taxonomy of clinical phenotypes is mixed with molecular heterogeneity. Of vital importance for refined clinical practice and improved intervention strategies is to define the hidden molecular distinct diseases using modern large-scale genomic approaches. Microarray omics technology has provided a powerful way to dissect hidden genetic heterogeneity of complex diseases. The aim of this study was thus to develop a bioinformatics approach to seek the transcriptional features leading to the hidden subtyping of a complex clinical phenotype. The basic strategy of the proposed method was to iteratively partition in two ways sample and feature space with super-paramagnetic clustering technique and to seek for hard and robust gene clusters that lead to a natural partition of disease samples and that have the highest functionally conceptual consensus evaluated with Gene Ontology.
We applied the proposed method to two publicly available microarray datasets of diffuse large B-cell lymphoma (DLBCL), a notoriously heterogeneous phenotype. A feature subset of 30 genes (38 probes) derived from analysis of the first dataset consisting of 4026 genes and 42 DLBCL samples identified three categories of patients with very different five-year overall survival rates (70.59%, 44.44% and 14.29% respectively; p = 0.0017). Analysis of the second dataset consisting of 7129 genes and 58 DLBCL samples revealed a feature subset of 13 genes (16 probes) that not only replicated the findings of the important DLBCL genes (e.g. JAW1 and BCL7A), but also identified three clinically similar subtypes (with 5-year overall survival rates of 63.13%, 34.92% and 15.38% respectively; p = 0.0009) to those identified in the first dataset. Finally, we built a multivariate Cox proportional-hazards prediction model for each feature subset and defined JAW1 as one of the most significant predictor (p = 0.005 and 0.014; hazard ratios = 0.02 and 0.03, respectively for two datasets) for both DLBCL cohorts under study.
Our results showed that the proposed algorithm is a promising computational strategy for peeling off the hidden genetic heterogeneity based on transcriptionally profiling disease samples, which may lead to an improved diagnosis and treatment of cancers.
PMCID: PMC2082044  PMID: 17888167
10.  Feature selection and survival modeling in The Cancer Genome Atlas 
International Journal of Nanomedicine  2013;8(Suppl 1):57-62.
Personalized medicine is predicated on the concept of identifying subgroups of a common disease for better treatment. Identifying biomarkers that predict disease subtypes has been a major focus of biomedical science. In the era of genome-wide profiling, there is controversy as to the optimal number of genes as an input of a feature selection algorithm for survival modeling.
Patients and methods
The expression profiles and outcomes of 544 patients were retrieved from The Cancer Genome Atlas. We compared four different survival prediction methods: (1) 1-nearest neighbor (1-NN) survival prediction method; (2) random patient selection method and a Cox-based regression method with nested cross-validation; (3) least absolute shrinkage and selection operator (LASSO) optimization using whole-genome gene expression profiles; or (4) gene expression profiles of cancer pathway genes.
The 1-NN method performed better than the random patient selection method in terms of survival predictions, although it does not include a feature selection step. The Cox-based regression method with LASSO optimization using whole-genome gene expression data demonstrated higher survival prediction power than the 1-NN method, but was outperformed by the same method when using gene expression profiles of cancer pathway genes alone.
The 1-NN survival prediction method may require more patients for better performance, even when omitting censored data. Using preexisting biological knowledge for survival prediction is reasonable as a means to understand the biological system of a cancer, unless the analysis goal is to identify completely unknown genes relevant to cancer biology.
PMCID: PMC3790279  PMID: 24098079
brain; feature selection; glioblastoma; personalized medicine; survival modeling; TCGA
11.  Survival Analysis by Penalized Regression and Matrix Factorization 
The Scientific World Journal  2013;2013:632030.
Because every disease has its unique survival pattern, it is necessary to find a suitable model to simulate followups. DNA microarray is a useful technique to detect thousands of gene expressions at one time and is usually employed to classify different types of cancer. We propose combination methods of penalized regression models and nonnegative matrix factorization (NMF) for predicting survival. We tried L1- (lasso), L2- (ridge), and L1-L2 combined (elastic net) penalized regression for diffuse large B-cell lymphoma (DLBCL) patients' microarray data and found that L1-L2 combined method predicts survival best with the smallest logrank P value. Furthermore, 80% of selected genes have been reported to correlate with carcinogenesis or lymphoma. Through NMF we found that DLBCL patients can be divided into 4 groups clearly, and it implies that DLBCL may have 4 subtypes which have a little different survival patterns. Next we excluded some patients who were indicated hard to classify in NMF and executed three penalized regression models again. We found that the performance of survival prediction has been improved with lower logrank P values. Therefore, we conclude that after preselection of patients by NMF, penalized regression models can predict DLBCL patients' survival successfully.
PMCID: PMC3655687  PMID: 23737722
12.  Alternative strategies for selecting subsets of predicting SNPs by LASSO-LARS procedure 
BMC Proceedings  2012;6(Suppl 2):S9.
The least absolute shrinkage and selection operator (LASSO) can be used to predict SNP effects. This operator has the desirable feature of including in the model only a subset of explanatory SNPs, which can be useful both in QTL detection and GWS studies. LASSO solutions can be obtained by the least angle regression (LARS) algorithm. The big issue with this procedure is to define the best constraint (t), i.e. the upper bound of the sum of absolute value of the SNP effects which roughly corresponds to the number of SNPs to be selected. Usai et al. (2009) dealt with this problem by a cross-validation approach and defined t as the average number of selected SNPs overall replications. Nevertheless, in small size populations, such estimator could give underestimated values of t. Here we propose two alternative ways to define t and compared them with the "classical" one.
The first (strategy 1), was based on 1,000 cross-validations carried out by randomly splitting the reference population (2,000 individuals with performance) into two halves. The value of t was the number of SNPs which occurred in more than 5% of replications. The second (strategy 2), which did not use cross-validations, was based on the minimization of the Cp-type selection criterion which depends on the number of selected SNPs and the expected residual variance.
The size of the subset of selected SNPs was 46, 189 and 64 for the classical approach, strategy 1 and 2 respectively. Classical and strategy 2 gave similar results and indicated quite clearly the regions were QTL with additive effects were located. Strategy 1 confirmed such regions and added further positions which gave a less clear scenario. Correlation between GEBVs estimated with the three strategies and TBVs in progenies without phenotypes were 0.9237, 0.9000 and 0.9240 for classical, strategy 1 and 2 respectively.
This suggests that the Cp-type selection criterion is a valid alternative to the cross-validations to define the best constraint for selecting subsets of predicting SNPs by LASSO-LARS procedure.
PMCID: PMC3363163  PMID: 22640825
13.  Development and Validation of Predictive Indices for a Continuous Outcome Using Gene Expression Profiles 
Cancer Informatics  2010;9:105-114.
There have been relatively few publications using linear regression models to predict a continuous response based on microarray expression profiles. Standard linear regression methods are problematic when the number of predictor variables exceeds the number of cases. We have evaluated three linear regression algorithms that can be used for the prediction of a continuous response based on high dimensional gene expression data. The three algorithms are the least angle regression (LAR), the least absolute shrinkage and selection operator (LASSO), and the averaged linear regression method (ALM). All methods are tested using simulations based on a real gene expression dataset and analyses of two sets of real gene expression data and using an unbiased complete cross validation approach. Our results show that the LASSO algorithm often provides a model with somewhat lower prediction error than the LAR method, but both of them perform more efficiently than the ALM predictor. We have developed a plug-in for BRB-ArrayTools that implements the LAR and the LASSO algorithms with complete cross-validation.
PMCID: PMC2879606  PMID: 20523915
regression model; gene expression; continuous outcome
14.  Molecular Pathways Differentiate Hepatitis C Virus (HCV) Recurrence from Acute Cellular Rejection in HCV Liver Recipients 
Molecular Medicine  2011;17(7-8):824-833.
Acute cellular rejection (ACR) and hepatitis C virus (HCV) recurrence (HCVrec) are common complications after liver transplantation (LT) in HCV patients, who share common clinical and histological features, making a differential diagnosis difficult. Fifty-three liver allograft samples from unique HCV LT recipients were studied using microarrays, including a training set (n = 32) and a validation set (n = 19). Two no-HCV-ACR samples from LT recipients were also included. Probe set intensity values were obtained using the robust multiarray average method (RMA) method. Analysis of variance identified statistically differentially expressed genes (P ≤ 0.005). The limma package was used to fit the mixed-effects models using a restricted maximum likelihood procedure. The last absolute shrinkage and selection operator (LASSO) model was fit with HCVrec versus ACR as the dependent variable predicted. N-fold cross-validation was performed to provide an unbiased estimate of generalization error. A total of 179 probe sets were differentially expressed among groups, with 71 exclusive genes between HCVrec and HCV-ACR. No differences were found within ACR group (HCV-ACR vs. no-HCV-ACR). Supervised clustering analysis displayed two clearly independent groups, and no-HCV-ACR clustered within HCV-ACR. HCVrec-related genes were associated with a cytotoxic T-cell profile, and HCV-ACR–related genes were associated with the inflammatory response. The best-fitting LASSO model classifier accuracy, including 15 genes, has an accuracy of 100% in the training set. N-fold cross-validation accuracy was 78.1%, and sensitivity, specificity and positive and negative predictive values were 50.0%, 90.9%, 71.4% and 80.0%, respectively. Arginase type II (ARG2), ethylmalonic encephalopathy 1 (ETHE1), transmembrane protein 176A (TMEM176A) and TMEM176B genes were significantly confirmed in the validation set. A molecular signature capable of distinguishing HCVrec and ACR in HCV LT recipients was identified and validated.
PMCID: PMC3146620  PMID: 21519635
15.  A four-marker signature of TNF-RII, TGF-α, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically resected melanoma 
E1694 tested GM2-KLH-QS21 vaccine versus high-dose interferon-α2b (HDI) as adjuvant therapy for operable stage IIB-III melanoma. We tested banked serum specimens from patients in the vaccine arm of E1694 for prognostic biomarkers.
Aushon Multiplex Platform was used to quantitate baseline serum levels of 115 analytes from 40 patients. Least absolute shrinkage and selection operator proportional hazard regression (Lasso PH) was used to select markers that are most informative for relapse-free survival (RFS) and overall survival (OS). Regular Cox PH models were then fit with the markers selected by the Lasso PH. Survival receiver operating characteristic (ROC) analysis was used to evaluate the ability of the models to predict 1-year RFS and 5-year OS.
Four markers that include Tumor Necrosis Factor alpha Receptor II (TNF-RII), Transforming Growth Factor alpha (TGF-α), Tissue Inhibitor of Metalloproteinases 1 (TIMP-1), and C-reactive protein (CRP) were found to be most informative for the prediction of OS (high levels correlate with worse prognosis). The dichotomized risk score based on the four markers could significantly separate the OS curves (p = 0.0005). When using the four-marker PH model to predict 5-year OS, we achieved an area under the curve (AUC) of 89% (cross validated AUC = 72%). High baseline TNF-RII was also significantly associated with worse RFS. The RFS with high (above median) TNF-RII was significantly lower than low TNF-RII (p = 0.01).
The biomarker signature consisting of TNFR-II, TGF-α, TIMP-1 and CRP is significantly prognostic of survival in patients with high-risk melanoma and warrants further investigation.
PMCID: PMC3909384  PMID: 24457057
Melanoma; Adjuvant; TNF-RII; TGF-α; TIMP-1; CRP; E1694
16.  Algorithm validation using multicolor phantoms 
Biomedical Optics Express  2012;3(6):1300-1311.
We present a framework for hyperspectral image (HSI) analysis validation, specifically abundance fraction estimation based on HSI measurements of water soluble dye mixtures printed on microarray chips. In our work we focus on the performance of two algorithms, the Least Absolute Shrinkage and Selection Operator (LASSO) and the Spatial LASSO (SPLASSO). The LASSO is a well known statistical method for simultaneously performing model estimation and variable selection. In the context of estimating abundance fractions in a HSI scene, the “sparse” representations provided by the LASSO are appropriate as not every pixel will be expected to contain every endmember. The SPLASSO is a novel approach we introduce here for HSI analysis which takes the framework of the LASSO algorithm a step further and incorporates the rich spatial information which is available in HSI to further improve the estimates of abundance. In our work here we introduce the dye mixture platform as a new benchmark data set for hyperspectral biomedical image processing and show our algorithm’s improvement over the standard LASSO.
PMCID: PMC3370971  PMID: 22741077
(000.5490) Probability theory, stochastic processes, and statistics; (110.4234) Multispectral and hyperspectral imaging; (120.0120) Instrumentation, measurement, and metrology; (170.0170) Medical optics and biotechnology; (170.3880) Medical and biological imaging; (180.0180) Microscopy; (350.4800) Optical standards and testing
17.  Incorporating pathway information into boosting estimation of high-dimensional risk prediction models 
BMC Bioinformatics  2009;10:18.
There are several techniques for fitting risk prediction models to high-dimensional data, arising from microarrays. However, the biological knowledge about relations between genes is only rarely taken into account. One recent approach incorporates pathway information, available, e.g., from the KEGG database, by augmenting the penalty term in Lasso estimation for continuous response models.
As an alternative, we extend componentwise likelihood-based boosting techniques for incorporating pathway information into a larger number of model classes, such as generalized linear models and the Cox proportional hazards model for time-to-event data. In contrast to Lasso-like approaches, no further assumptions for explicitly specifying the penalty structure are needed, as pathway information is incorporated by adapting the penalties for single microarray features in the course of the boosting steps. This is shown to result in improved prediction performance when the coefficients of connected genes have opposite sign. The properties of the fitted models resulting from this approach are then investigated in two application examples with microarray survival data.
The proposed approach results not only in improved prediction performance but also in structurally different model fits. Incorporating pathway information in the suggested way is therefore seen to be beneficial in several ways.
PMCID: PMC2647532  PMID: 19144132
18.  Predicting the survival time for diffuse large B-cell lymphoma using microarray data 
The present study was conducted to predict survival time in patients with diffuse large B-cell lymphoma, DLBCL, based on microarray data using Cox regression model combined with seven dimension reduction methods. This historical cohort included 2042 gene expression measurements from 40 patients with DLBCL. In order to predict survival, a combination of Cox regression model was used with seven methods for dimension reduction or shrinkage including univariate selection, forward stepwise selection, principal component regression, supervised principal component regression, partial least squares regression, ridge regression and Losso. The capacity of predictions was examined by three different criteria including log rank test, prognostic index and deviance. MATLAB r2008a and RKWard software were used for data analysis. Based on our findings, performance of ridge regression was better than other methods. Based on ridge regression coefficients and a given cut point value, 16 genes were selected. By using forward stepwise selection method in Cox regression model, it was indicated that the expression of genes GENE3555X and GENE3807X decreased the survival time (P=0.008 and P=0.003, respectively), whereas the genes GENE3228X and GENE1551X increased survival time (P=0.002 and P<0.001, respectively). This study indicated that ridge regression method had higher capacity than other dimension reduction methods for the prediction of survival time in patients with DLBCL. Furthermore, a combination of statistical methods and microarray data could help to detect influential genes in survival.
PMCID: PMC3410377  PMID: 23173013
Lymphoma; gene expression; microarray; survival analysis; dimension reduction; ridge regression
19.  A chain reaction approach to modelling gene pathways 
Translational cancer research  2012;1(2):61-73.
Of great interest in cancer prevention is how nutrient components affect gene pathways associated with the physiological events of puberty. Nutrient-gene interactions may cause changes in breast or prostate cells and, therefore, may result in cancer risk later in life. Analysis of gene pathways can lead to insights about nutrient-gene interactions and the development of more effective prevention approaches to reduce cancer risk. To date, researchers have relied heavily upon experimental assays (such as microarray analysis, etc.) to identify genes and their associated pathways that are affected by nutrient and diets. However, the vast number of genes and combinations of gene pathways, coupled with the expense of the experimental analyses, has delayed the progress of gene-pathway research. The development of an analytical approach based on available test data could greatly benefit the evaluation of gene pathways, and thus advance the study of nutrient-gene interactions in cancer prevention. In the present study, we have proposed a chain reaction model to simulate gene pathways, in which the gene expression changes through the pathway are represented by the species undergoing a set of chemical reactions. We have also developed a numerical tool to solve for the species changes due to the chain reactions over time. Through this approach we can examine the impact of nutrient-containing diets on the gene pathway; moreover, transformation of genes over time with a nutrient treatment can be observed numerically, which is very difficult to achieve experimentally. We apply this approach to microarray analysis data from an experiment which involved the effects of three polyphenols (nutrient treatments), epigallo-catechin-3-O-gallate (EGCG), genistein, and resveratrol, in a study of nutrient-gene interaction in the estrogen synthesis pathway during puberty.
In this preliminary study, the estrogen synthesis pathway was simulated by a chain reaction model. By applying it to microarray data, the chain reaction model computed a set of reaction rates to examine the effects of three polyphenols (EGCG, genistein, and resveratrol) on gene expression in this pathway during puberty. We first performed statistical analysis to test the time factor on the estrogen synthesis pathway. Global tests were used to evaluate an overall gene expression change during puberty for each experimental group. Then, a chain reaction model was employed to simulate the estrogen synthesis pathway. Specifically, the model computed the reaction rates in a set of ordinary differential equations to describe interactions between genes in the pathway (A reaction rate K of A to B represents gene A will induce gene B per unit at a rate of K; we give details in the “method” section). Since disparate changes of gene expression may cause numerical error problems in solving these differential equations, we used an implicit scheme to address this issue. We first applied the chain reaction model to obtain the reaction rates for the control group. A sensitivity study was conducted to evaluate how well the model fits to the control group data at Day 50. Results showed a small bias and mean square error. These observations indicated the model is robust to low random noises and has a good fit for the control group. Then the chain reaction model derived from the control group data was used to predict gene expression at Day 50 for the three polyphenol groups. If these nutrients affect the estrogen synthesis pathways during puberty, we expect discrepancy between observed and expected expressions. Results indicated some genes had large differences in the EGCG (e.g., Hsd3b and Sts) and the resveratrol (e.g., Hsd3b and Hrmt12) groups.
In the present study, we have presented (I) experimental studies of the effect of nutrient diets on the gene expression changes in a selected estrogen synthesis pathway. This experiment is valuable because it allows us to examine how the nutrient-containing diets regulate gene expression in the estrogen synthesis pathway during puberty; (II) global tests to assess an overall association of this particular pathway with time factor by utilizing generalized linear models to analyze microarray data; and (III) a chain reaction model to simulate the pathway. This is a novel application because we are able to translate the gene pathway into the chemical reactions in which each reaction channel describes gene-gene relationship in the pathway. In the chain reaction model, the implicit scheme is employed to efficiently solve the differential equations. Data analysis results show the proposed model is capable of predicting gene expression changes and demonstrating the effect of nutrient-containing diets on gene expression changes in the pathway.
One of the objectives of this study is to explore and develop a numerical approach for simulating the gene expression change so that it can be applied and calibrated when the data of more time slices are available, and thus can be used to interpolate the expression change at a desired time point without conducting expensive experiments for a large amount of time points. Hence, we are not claiming this is either essential or the most efficient way for simulating this problem, rather a mathematical/numerical approach that can model the expression change of a large set of genes of a complex pathway. In addition, we understand the limitation of this experiment and realize that it is still far from being a complete model of predicting nutrient-gene interactions. The reason is that in the present model, the reaction rates were estimated based on available data at two time points; hence, the gene expression change is dependent upon the reaction rates and a linear function of the gene expressions. More data sets containing gene expression at various time slices are needed in order to improve the present model so that a non-linear variation of gene expression changes at different time can be predicted.
PMCID: PMC3431024  PMID: 22943042
Chain reaction; gene expression change; estrogen synthesis pathway; nutrient diets
20.  Validation of differential gene expression algorithms: Application comparing fold-change estimation to hypothesis testing 
BMC Bioinformatics  2010;11:63.
Sustained research on the problem of determining which genes are differentially expressed on the basis of microarray data has yielded a plethora of statistical algorithms, each justified by theory, simulation, or ad hoc validation and yet differing in practical results from equally justified algorithms. Recently, a concordance method that measures agreement among gene lists have been introduced to assess various aspects of differential gene expression detection. This method has the advantage of basing its assessment solely on the results of real data analyses, but as it requires examining gene lists of given sizes, it may be unstable.
Two methodologies for assessing predictive error are described: a cross-validation method and a posterior predictive method. As a nonparametric method of estimating prediction error from observed expression levels, cross validation provides an empirical approach to assessing algorithms for detecting differential gene expression that is fully justified for large numbers of biological replicates. Because it leverages the knowledge that only a small portion of genes are differentially expressed, the posterior predictive method is expected to provide more reliable estimates of algorithm performance, allaying concerns about limited biological replication. In practice, the posterior predictive method can assess when its approximations are valid and when they are inaccurate. Under conditions in which its approximations are valid, it corroborates the results of cross validation. Both comparison methodologies are applicable to both single-channel and dual-channel microarrays. For the data sets considered, estimating prediction error by cross validation demonstrates that empirical Bayes methods based on hierarchical models tend to outperform algorithms based on selecting genes by their fold changes or by non-hierarchical model-selection criteria. (The latter two approaches have comparable performance.) The posterior predictive assessment corroborates these findings.
Algorithms for detecting differential gene expression may be compared by estimating each algorithm's error in predicting expression ratios, whether such ratios are defined across microarray channels or between two independent groups.
According to two distinct estimators of prediction error, algorithms using hierarchical models outperform the other algorithms of the study. The fact that fold-change shrinkage performed as well as conventional model selection criteria calls for investigating algorithms that combine the strengths of significance testing and fold-change estimation.
PMCID: PMC3224549  PMID: 20109217
21.  Regularized estimation of large-scale gene association networks using graphical Gaussian models 
BMC Bioinformatics  2009;10:384.
Graphical Gaussian models are popular tools for the estimation of (undirected) gene association networks from microarray data. A key issue when the number of variables greatly exceeds the number of samples is the estimation of the matrix of partial correlations. Since the (Moore-Penrose) inverse of the sample covariance matrix leads to poor estimates in this scenario, standard methods are inappropriate and adequate regularization techniques are needed. Popular approaches include biased estimates of the covariance matrix and high-dimensional regression schemes, such as the Lasso and Partial Least Squares.
In this article, we investigate a general framework for combining regularized regression methods with the estimation of Graphical Gaussian models. This framework includes various existing methods as well as two new approaches based on ridge regression and adaptive lasso, respectively. These methods are extensively compared both qualitatively and quantitatively within a simulation study and through an application to six diverse real data sets. In addition, all proposed algorithms are implemented in the R package "parcor", available from the R repository CRAN.
In our simulation studies, the investigated non-sparse regression methods, i.e. Ridge Regression and Partial Least Squares, exhibit rather conservative behavior when combined with (local) false discovery rate multiple testing in order to decide whether or not an edge is present in the network. For networks with higher densities, the difference in performance of the methods decreases. For sparse networks, we confirm the Lasso's well known tendency towards selecting too many edges, whereas the two-stage adaptive Lasso is an interesting alternative that provides sparser solutions. In our simulations, both sparse and non-sparse methods are able to reconstruct networks with cluster structures. On six real data sets, we also clearly distinguish the results obtained using the non-sparse methods and those obtained using the sparse methods where specification of the regularization parameter automatically means model selection. In five out of six data sets, Partial Least Squares selects very dense networks. Furthermore, for data that violate the assumption of uncorrelated observations (due to replications), the Lasso and the adaptive Lasso yield very complex structures, indicating that they might not be suited under these conditions. The shrinkage approach is more stable than the regression based approaches when using subsampling.
PMCID: PMC2808166  PMID: 19930695
22.  Resampling procedures to identify important SNPs using a consensus approach 
BMC Proceedings  2011;5(Suppl 9):S59.
Our goal is to identify common single-nucleotide polymorphisms (SNPs) (minor allele frequency > 1%) that add predictive accuracy above that gained by knowledge of easily measured clinical variables. We take an algorithmic approach to predict each phenotypic variable using a combination of phenotypic and genotypic predictors. We perform our procedure on the first simulated replicate and then validate against the others. Our procedure performs well when predicting Q1 but is less successful for the other outcomes. We use resampling procedures where possible to guard against false positives and to improve generalizability. The approach is based on finding a consensus regarding important SNPs by applying random forests and the least absolute shrinkage and selection operator (LASSO) on multiple subsamples. Random forests are used first to discard unimportant predictors, narrowing our focus to roughly 100 important SNPs. A cross-validation LASSO is then used to further select variables. We combine these procedures to guarantee that cross-validation can be used to choose a shrinkage parameter for the LASSO. If the clinical variables were unavailable, this prefiltering step would be essential. We perform the SNP-based analyses simultaneously rather than one at a time to estimate SNP effects in the presence of other causal variants. We analyzed the first simulated replicate of Genetic Analysis Workshop 17 without knowledge of the true model. Post-conference knowledge of the simulation parameters allowed us to investigate the limitations of our approach. We found that many of the false positives we identified were substantially correlated with genuine causal SNPs.
PMCID: PMC3287897  PMID: 22373247
23.  Kernel based methods for accelerated failure time model with ultra-high dimensional data 
BMC Bioinformatics  2010;11:606.
Most genomic data have ultra-high dimensions with more than 10,000 genes (probes). Regularization methods with L1 and Lp penalty have been extensively studied in survival analysis with high-dimensional genomic data. However, when the sample size n ≪ m (the number of genes), directly identifying a small subset of genes from ultra-high (m > 10, 000) dimensional data is time-consuming and not computationally efficient. In current microarray analysis, what people really do is select a couple of thousands (or hundreds) of genes using univariate analysis or statistical tests, and then apply the LASSO-type penalty to further reduce the number of disease associated genes. This two-step procedure may introduce bias and inaccuracy and lead us to miss biologically important genes.
The accelerated failure time (AFT) model is a linear regression model and a useful alternative to the Cox model for survival analysis. In this paper, we propose a nonlinear kernel based AFT model and an efficient variable selection method with adaptive kernel ridge regression. Our proposed variable selection method is based on the kernel matrix and dual problem with a much smaller n × n matrix. It is very efficient when the number of unknown variables (genes) is much larger than the number of samples. Moreover, the primal variables are explicitly updated and the sparsity in the solution is exploited.
Our proposed methods can simultaneously identify survival associated prognostic factors and predict survival outcomes with ultra-high dimensional genomic data. We have demonstrated the performance of our methods with both simulation and real data. The proposed method performs superbly with limited computational studies.
PMCID: PMC3019227  PMID: 21176134
24.  Combining least absolute shrinkage and selection operator (LASSO) and principal-components analysis for detection of gene-gene interactions in genome-wide association studies 
BMC Proceedings  2009;3(Suppl 7):S62.
Variable selection in genome-wide association studies can be a daunting task and statistically challenging because there are more variables than subjects. We propose an approach that uses principal-component analysis (PCA) and least absolute shrinkage and selection operator (LASSO) to identify gene-gene interaction in genome-wide association studies. A PCA was used to first reduce the dimension of the single-nucleotide polymorphisms (SNPs) within each gene. The interaction of the gene PCA scores were placed into LASSO to determine whether any gene-gene signals exist. We have extended the PCA-LASSO approach using the bootstrap to estimate the standard errors and confidence intervals of the LASSO coefficient estimates. This method was compared to placing the raw SNP values into the LASSO and the logistic model with individual gene-gene interaction. We demonstrated these methods with the Genetic Analysis Workshop 16 rheumatoid arthritis genome-wide association study data and our results identified a few gene-gene signals. Based on our results, the PCA-LASSO method shows promise in identifying gene-gene interactions, and, at this time we suggest using it with other conventional approaches, such as generalized linear models, to narrow down genetic signals.
PMCID: PMC2795963  PMID: 20018056
25.  Sparse logistic regression with a L1/2 penalty for gene selection in cancer classification 
BMC Bioinformatics  2013;14:198.
Microarray technology is widely used in cancer diagnosis. Successfully identifying gene biomarkers will significantly help to classify different cancer types and improve the prediction accuracy. The regularization approach is one of the effective methods for gene selection in microarray data, which generally contain a large number of genes and have a small number of samples. In recent years, various approaches have been developed for gene selection of microarray data. Generally, they are divided into three categories: filter, wrapper and embedded methods. Regularization methods are an important embedded technique and perform both continuous shrinkage and automatic gene selection simultaneously. Recently, there is growing interest in applying the regularization techniques in gene selection. The popular regularization technique is Lasso (L1), and many L1 type regularization terms have been proposed in the recent years. Theoretically, the Lq type regularization with the lower value of q would lead to better solutions with more sparsity. Moreover, the L1/2 regularization can be taken as a representative of Lq (0
In this work, we investigate a sparse logistic regression with the L1/2 penalty for gene selection in cancer classification problems, and propose a coordinate descent algorithm with a new univariate half thresholding operator to solve the L1/2 penalized logistic regression. Experimental results on artificial and microarray data demonstrate the effectiveness of our proposed approach compared with other regularization methods. Especially, for 4 publicly available gene expression datasets, the L1/2 regularization method achieved its success using only about 2 to 14 predictors (genes), compared to about 6 to 38 genes for ordinary L1 and elastic net regularization approaches.
From our evaluations, it is clear that the sparse logistic regression with the L1/2 penalty achieves higher classification accuracy than those of ordinary L1 and elastic net regularization approaches, while fewer but informative genes are selected. This is an important consideration for screening and diagnostic applications, where the goal is often to develop an accurate test using as few features as possible in order to control cost. Therefore, the sparse logistic regression with the L1/2 penalty is effective technique for gene selection in real classification problems.
PMCID: PMC3718705  PMID: 23777239
Gene selection; Sparse logistic regression; Cancer classification

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